We have investigated the mechanisms of oncogene regulation in human malignancies. A large body of evidence has implicated the c-myc oncogene in normal cell growth and differentiation as well as in the development of a wide range of human cancers. This project is designed to study both the mechanisms of transcriptional regulation of the c-myc gene and to determine the role of c-Myc protein in the development of neoplastic disease. The major goals are the following: A)Transcriptional regulation of the c-myc oncogene in normal and neoplastic cells. We have identified several nuclear DNA binding proteins and their recognition sequences within the c-myc gene. Cloning and characterization of these transcription factors will allow us to establish their role in the regulation of c-myc oncogene expression in normal and cancer cells. B)The role of the c-Myc protein in normal and neoplastic growth. The product of the c-myc gene is a nuclear phosphoprotein that has been implicated in cell differentiation, apoptosis, and in the development of human tumors. c-Myc functions as a transcription factor, however, the mechanism of c-Myc regulation remains unknown. We have established that c-Myc associates with microtubules in vivo and in vitro, and we plan to examine the involvement of microtubules in regulation of c-Myc transcriptional activity and its possible role in the neoplastic disease.